Leqembi
lecanemab
Species
Monkey
Longest study
39 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey only
“The pivotal (4- and 39-week) toxicity studies of lecanemab were conducted in cynomolgus monkey, the only pharmacologically relevant species.”
Why that species
Cynomolgus IgG1 sequence similar to human IgG1; monkeys predictive of antibody pharmacokinetics
“Cynomolgus monkey IgG1 has a similar sequence to human IgG1 and cynomolgus monkeys were considered generally predictive of the pharmacokinetics of such antibodies in humans.”
Surrogate molecule
Yes: rodent surrogate mAb158, used for microhemorrhage studies in mice because lecanemab induces anti-drug antibodies in rodents
“Given the production of anti-drug antibodies against lecanemab in rodents, microhemorrhage studies were conducted with the rodent surrogate, mAb158.”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“In the 39-week study (0, 15, 50, and 100 mg/kg/week) (with 2-week recovery)”
Pivotal GLP studies
4-week and 39-week cynomolgus monkey studies
“The pivotal (4- and 39-week) toxicity studies of lecanemab were conducted in cynomolgus monkey”
Route in tox
Intravenous bolus, weekly
“In both studies, lecanemab was administered weekly by intravenous bolus injection.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6)
“Studies evaluating genotoxicity of biotechnology products, are not mandatory in accordance with ICH S6 guideline”
Carcinogenicity
Not conducted; not necessary because of neutralizing anti-drug antibodies in rodents to lecanemab and its surrogate mAb158
“On March 19, 2014, the applicant was informed that a carcinogenicity assessment of lecanemab would not be necessary based on the development of neutralizing anti-drug antibodies in rodents treated with lecanemab or the mouse surrogate, mAb158.”
Reproductive & developmental
Not conducted; reproductive and developmental toxicology studies not required
“No reproductive and developmental toxicology studies were conducted with lecanemab. The sponsor was informed on November 6, 2012, that reproductive and development toxicology studies are not required”
Safety pharmacology
No stand-alone safety pharmacology studies (ICH S6(R1) and S7A)
“In accordance with ICH guidelines S6(R1) and S7A no stand-alone safety pharmacology studies were performed.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Leqembi don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for monoclonal antibodies outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: NOAEL 100 mg/kg once weekly in the 39-week study (EMA assessment report, p. 31)
NOAEL / key findings
NOAEL 100 mg/kg once weekly in the 39-week study
“In the 39-week intermittent intravenous dose toxicity study with 13-week recovery period, NOAEL (be 100 mg/kg, once a week) corresponded to mean AUC(0-384h) for males and females of”
Risksopen answer page →
Immune & cytokine safety
No ADAs detected in monkey IV repeat-dose and SC local irritation studies
“No ADAs to lecanemab were detected in the serum samples from i.v. repeat-dose toxicity and s.c. local irritation studies in cynomolgus monkeys.”
Biodistribution & persistence
CSF-to-plasma ratios 0.53, 0.44 and 0.30% at 1, 5 and 15 mg/kg (AUC-based)
“CSF-to-plasma ratios were 0.53, 0.44 and 0.30% at 1, 5 and 15 mg/kg based on AUC0-168h, respectively.”
Modality-specific risk
Cerebral microhemorrhage; high binding to human FcγRI and FcγRIII may contribute
“Lecanemab also demonstrated high binding affinity for human FcγRs (FcγRI and FcγRIII), which is thought be involved in amyloid beta clearance but may also contribute to cerebral microhemorrhage.”